Pigmentation results from the synthesis and distribution of melanic pigments most notably in the skin, the hair and the pigmentary epithelium of the iris. Thus, the color of the skin, the hair and the eyes depends principally on the types of pigments present and their concentrations.
Melanins are macromolecules produced in melanosomes, i.e. specialized intracellular organelles contained in melanocytes, by the addition or condensation of monomers formed from tyrosine (eumelanin) or of tyrosine and cysteine (pheomelanin). The mechanism by which melanins are synthesized, or melanogenesis, is particularly complex and involves various enzymes, principally tyrosinase and the tyrosine related protein (tyrosinase-related protein-1 or Tyrp-1).
Melanosome maturation can be broken down into four stages on the basis of morphological criteria. Stage I corresponds to a compartment delimited by a membrane with a variable quantity of intraluminal membranes. Stage II is an ellipsoidal structure with characteristic protein-like striations. Melanin is detected from stage III by electron-dense deposits along the striations. Stage IV is an electron-dense structure in which the internal striations are no longer visible and corresponding to the mature melanosome ready to be transferred to the keratinocytes (Van Den Bossche et al., 2006, Traffic, 7, 769-778; Raposo and Marks, Nat Rev Mol Cell Biol. October 2007; 8(10): 786-797).
During the process of biogenesis, stage III and IV melanosomes are obtained by the transfer of enzymes that are key to melanin synthesis in the pre-melanosomes (Raposo et al., 2001, J. Cell Biol. 152, 809-824). This type of transfer requires in particular the participation of three adaptor protein (AP) complexes, named AP-1 to AP-3, which are heterotetramers having the role of recruiting enzymes in the transport vesicles.
Although the melanin in the skin represents suitable protection against UV radiation, darker or overpigmented skin such as hyperpigmentation (e.g. chloasma or melasma), freckles (ephelides), age spots (lentigines), sun spots or seborrheic keratosis, may result in serious aesthetic problems. These pigment spots may be induced by melanocyte dysfunction or may be due to an accident, e.g. by photosensitization or post-lesion scarring. The sun very frequently plays an important role and prevention can be achieved, in particular, by regular sun protection with a high light protection factor.
In order to remove unattractive pigment spots, various possibilities are available, such as lasers, dermabrasion or other electrosurgical methods and bleaching creams comprising depigmentation or whitening substances. The latter alternative has the advantage that it is significantly less expensive and more pleasant for the patient.
A whitening molecule acts on skin melanocytes and interferes with one or more stages of melanogenesis. Known depigmentation substances are in particular hydroquinone and its derivatives, ascorbic acid and its derivatives, placental extracts, kojic acid, niacinamide, vitamin C, rucinol, arbutin, plants extracts such as from Morus alba or Phyllanthus emblica, iminophenols (WO 99/22707), the combination of carnitine and quinone (DE 19806947), amino-phenol amide derivatives (FR 2772607) or benzothiazole derivatives (WO 99/24035). However, these substances present various disadvantages such as low efficiency, instability of the formulations, short shelf life, nonspecific action, or toxic, irritating or allergenic properties.
In the last few years, new approaches to whiten skin have appeared using antisense oligonucleotides or peptide inhibitors. For example, it was envisaged to treat hyperpigmentation with antisense oligonucleotides regulating the expression of tyrosinase (FR 2804960), peptides inhibiting the interaction between the AP-2 or AP-3 complex and the tyrosinase (WO 2009/010356) or directly inhibiting the tyrosinase (WO 2009/003034).
It was known that a kinesin, named KIF13A, was able to interact with a sub-unit of AP-1 (Nakagawa et al., Cell, 2000, vol. 103, 569-581) and the inventors previously showed that the synthesis of melanic pigments could be efficiently decreased with a nucleic acid inhibiting the expression of a sub-unit of AP-1 adaptor complex which interacts with kinesin KIF13A (WO 2009/141541). This nucleic acid was not only able to disrupt the transport of melanogenesis enzymes of the endosomes toward the pre-melanosomes, thus blocking the maturation of these organelles, but also was able to decrease the expression of melanogenesis enzymes. It thus constitutes an effective depigmentation agent. However, stability, formulation and route of administration remain tricky when using nucleic acid as dermatological or cosmetic agent.
Thus, there is still a need for novel skin whitening agents that are able to disrupt the transport of melanogenesis enzymes in the pre-melanosomes and thus have a high effectiveness, but also good formulation properties.